We propose to conduct a series of experiments designed to extend our original findings from the first year of this grant concerning the relationship between polydrug abuse and euphoria in human subjects. Specific drug combinations planned for study include: cocaine and marihuana, marihuana and ethanol, and alprazolam and ethanol. Drug- induced alterations in electroencephalographic (EEG) activity, evoked potentials, physiological responses, behavioral states, and cognitive function after both acute drug administration and during drug self- administration will be studied. Regional changes in brain electrical activity during intoxication will be quantified using topographic mapping procedures to determine if neurophysiologic changes precede cocaine-and marihuana-seeking behavior and if cocaine-induced euphoria is qualitatively different from marihuana-induced euphoria. EEG topographic mapping procedures will also be used to determine the extent to which prior exposure to marihuana affects the acute cocaine response and subsequent cocaine self-administration. Potentially new pharmacological therapies for cocaine abuse will be explored by evaluating the effects of acute administration of amantadine, benztropine, or trazodone on cocaine- induced EEG and behavioral responses. Studies will be conducted using multiple drug combinations and within-subject designs under double-blind conditions. Plasma drug levels will also be measured to determine if drug-induced euphoria is directly correlated with specific plasma drug levels and to determine if the nature of the observed drug interactions is due to alterations in pharmacokinetic profiles. We will also address the issue of whether acute tolerance or sensitization to cocaine's effects on brainstem auditory and visual evoked potentials, P300 evoked potentials, and performance on a divided attention task. A more detailed analysis of P300 activity will be accomplished by acquiring single sweep data to determine whether latency shifts or amplitude reductions occur after cocaine administration. Finally, to complete the spectrum of our interest in polydrug abuse, we propose to evaluate inpatients undergoing detoxification from polydrug dependence using the above series of neurophysiological and cognitive tasks to determine if such measures can be used to monitor progress and predict treatment outcome. Data obtained from these experiments will enhance our basic understanding of the nature of the interactions between two drugs of abuse and how this relationship alters drug reinforcement and drug-seeking behavior. In addition, the issue of vulnerability to drug abuse will be explored by correlating pre-drug control measures of EEG and evoked potential responses with the subsequent cocaine- marihuana- and alprazolam-induced responses. Results from the drug self-administration and the detoxification experiments will have direct applications in the management and treatment of drug abuse.